Phenyl granatane derivatives



United States Patent O 9 Ciairns. 61. 260-293) This invention relates to a series of new 3-beta-phenylgranatane derivatives having utility as blood pressure increasing agents. This invention also relates to the process for preparing and using these compounds. More particularly, this invention relates to S-beta-phenylgranatane derivatives of the formula:

N l R os s wherein R is hydrogen, alkyl, alkenyl, aralkyl or aryl and A is a carbonyl group CO), a hydroxymethylene group CHOH), its ether or ester derivative, a methylene group CH or a methine group The 3-beta-phenylgranatane derivatives of the invention can be produced by condensing 3-phenyl-glutardialdehyde with acetone-dicarboxylic acid and a primary amine of the formula R-NH wherein R is as above, the CO group of the 7-beta-phenyl-norgranatanone-(3) thus obtained is thereafter reduced in the conventional manner to a CH or CHOH group. The secondary OH group may be etherified or esterified or the OH group can be split off with the formation of a double bond to the adjacent carbon atom.

The condensation of the 3-phenyl-glutardialdehyde with the amine and the acetone-dicarboxylic acid is carried out under the conditions of the Robinson-Schiipf synthesis, under conditions effective to result in condensation and the formation of the phenyl-norgranatone, i.e., in a weakly acid reaction medium, preferably at room temperature or at a slightly elevated temperature of up to 60 C. and

in water or in a mixture of water and acetone. The reaction is set forth in the following equation:

11000 COOH (I) CH2 CH2 NH: CHO CHO N (I,A=CO) I R I I CH2 Hz R (3H tHs C0115 The phenyl-norgranatanones-(3) of Formula I (A=CO) are classified as the 7-beta-series of phenyl-norgranatanones-(3) (Alder et al., Ann., 620, 1959, page 74).

The 3-phenyl-glutardialdehyde employed in the condensation can be prepared by known methods. Thus, 3-phenyl-glutardialdehyde can be made by the method of Longley et al. (J. Am. Soc., 2, 3079 (1950), and 74, 2012 (1952)). According to Longley, cinnamaldehyde is reacted with vinyl-ethylether, the 2-ethoXy-4-phenyl-3,4-

3,228,948 Patented Jan. 11, 1966 dihydro-ZH-pyrane (II) thus obtained saponified. This series of reactions is illustrated as follows:

It is not, however, essential to isolate the 3-phenylglutardialdehyde from the reaction mixture, the hydrolyzate of the 2-ethoxy-4-pheny1-3,4-dihydro-2H-pyrane (II), which is present in an acid aqueous solution, can be directly employed in the Robinson-Schtipf synthesis, or, alternatively, compound II can be reacted, without prior hydrolysis, with the amine RNH and acetone-dicarboxylic acid at a pH of 1-3, whereby the acid reaction medium will act to hydrolyze compound II. v

The conversion of the 7-beta-phenyl-norgranatanones: (3) of Formula I (A CO) to the 3-beta-phenyl-norgranatanes of Formula I (A=CH can be conducted by reducing the carbonyl group in the conventional manner as, for instance, by the Wolif-Kishner Reduction Method. When the reduction of compounds I (A=CO) is conducted using sodium in an alcohol as reducing agent, the N-substituted 7-beta-phenyl-norgranatanols-(3-beta) of Formula I (A=CHOH with the OH group in the beta-position) is produced but when the reduction is conducted employing a complex metal hydride or catalytically activated hydrogen as reducing agent, the isomeric N-substituted 7-beta-phenyl-norgranatanols-(3-alpha) of Formula I (A CHOH with the OH group in the alpha-position) is obtained.

The granatanol derivatives produced in this manner (Formula I, A CHOH) can be converted into the corresponding ether or ester, Formula I (A=CHOR' or CHOCOR respectively, wherein R'represents alkyl, aralkyl or aryl). The etherification or esterification is con-' ducted by the conventional methods, as for example by the conversion of alcohol or of the sodium salt thereof (using alkyl halides or acid halides).

The 7-bcta-phenyl-norgranatane derivatives of Formula I wherein A represents a methine group can be prepared by splitting off the OH group of the granatanol derivative (Formula I, A CHOH) giving rise to a double bond to the adjacent carbon atom. The splitting off of the water is carried out by conventional methods, as for example, by reacting the alcohol (Formula I, A CHOH) with thionyl chloride and thereafter treating the halogen derivative (Formula -I, A=CHC1) produced as an intermediate with a base.

The 3-beta-phenylgranatane derivatives of Formula I in accordance with the invention have been found to possess blood pressure raising properties which are based on their effect on the central nervous system. The mechanism by which the blood pressure increasing action occurs is believed to arise from stimulation of the vasomotor center since it does not take place when the vasomotor system is surgically removed. The hypertensive effective of the compounds of the invention, therefore, cannot be compared with the sympathicomimetics of the prior art which act to increase the blood pressure by means of peripheral vasoconstriction.

In comparison with known central nervous stimulants as, for example, Cardiazol (pentamethylene-tetrazol) and Gevilon (beta,beta-pentamethylenc-gamma-hydroxy-sodium butyrate), the compounds of the invention possess no analeptic activity, but nevertheless act to increase the blood pressure in rats, rabbits, and cats in urethane narcosis. Cardiazol or Gevilon are ineflective in this connection even when administered in doses large enoughto produce cramps.

The products of the invention represent chemotherapeutic agents lending themselves by virtue of their properties in increasing blood pressure without concomitant analeptic activity, constitute a qualitatively new type of therapeutic agent which can be used with relative safety in the treatment of hypotonia.

The following examples are drawn to illustrate novel compounds of this invention and Will serve to illustrate procedures for the preparation of the compounds. It will be readily apparent to one skilled in the art that variations of these procedures are possible.

Example I.7-beta-phenyl-granatanone-(3) (7-betaphenyl-pseudo-palletierine) Method 1.80 grams of 2-ethoxy-4-phenyl-3,4-dihydro-ZH-pyrane (prepared by the method of Longley et a1. [J. Amer. Soc., 72, 3079 (1950)] by heating cinnamaldehyde and vinyl-ethylether in an autoclave to 180.

C.) are dissolved in 200 ml. acetone and refluxed for one hour with 36 ml. water and 8 ml. concentrated hydrochloric acid. The solution of 3-phenyl-glutardialdehyde obtained in this manner is cooled and added dropwise with agitation to a solution of 57.3 g. acetone dicarboxylic acid in 1200 ml. acetone, 26.5 g. methylamine hydrochloride and 13.5 g. sodium acetate (trihydrate) in 200 ml. water. The pH value of the mixture amounts to 3.8. The mixture is permitted to stand four days at room temperature and thereafter it is shaken with concentrated potassium carbonate solution, saturated with solid sodium chloride and extracted with chloroform. The extract is dried and concentrated and the concentrate is fractionated. At a temperature of l40-l48 C. (0.5 mm. Hg), 17.0 g. of 7-beta-phenyl-pseudopalletierine distill over (18.9% yield). This fraction hardens and melts, after repeated recrystallization from petroleum ether at 135-137 C. The Water soluble hydrochloride of 7-betaphenyl-pseudopelletierine is obtained by adding ethereal hydrochloric acid to an alcoholic solution ;of 7-beta-phenyl-pseudopelletierine. The hydrochloride, after repeated recrystallization from alcohol, melts at 235 C. (with decomposition).

Method 2.102.1 grams of 2-ethoxy-4-phenyl-3,4-dihydro-2H-pyrane are dissolved in 2 liters of acetone and the solution mixed with a solution of 75 g. acetonedicarboxylic acid, 38.7 g. methylamine hydrochloride, and 28.2 g. sodium acetate (trihydrate) in 250 ml. water. The mixture is heated under reflux for 8 hours with agitation. It is thereafter concentrated to A of the volume, alkalinized with caustic soda solution and the alkaline mixture shaken repeatedly with chloroform. The extract is dried and concentrated and the concentrate distilled, 13.6 grams of 7-beta-phenyl-pseudopelletierine and thusobtained having a B.P. M of 160-200 C. (11.9% yield).

Example 2.3-beta-phenyl-granatane ing a B.P. 02 of 125-145 C. The recovered fraction partially crystallizes. By suction filtering, 11.2 g. of solid 3-beta-phenyl-granatane could be obtained. The yield amounts to 79.5%. Because of its great solubility, the base cannot be recrystallized from the usual organic solvents. The corresponding hydrochloride melts at 197-19 9 C. (from methyl ethyl ketone).

Example 3.--7-beta-phenyl-granatanol- (3-alpha) 15.9 grams of the 7-beta-phenyl-psuedopelletierine obtained according to the procedure of Example 1 are dissolved in 150 ml. absolute tetrahydrofuran and slowly added drop-wise and with agitation to a solution of 1.7 g. lithium aluminum hydride in 200 ml. absolute tetrahydroturan. Thereafter the mixture is heated for another 5 hours under reflux. 20 ml. sodium chloride solution are added slowly (dropby drop at first) with stirring to the reflux mixture. The precipitated aluminum hydroxide is removed by suction filtering, and the filtrate dried and concentrated. Distillation of the concentrate produces 11.7 grams of 7-beta-phenyl-granatanol-(3-alpha) having a boiling point M of 160-170 C. The yield amounts to 72.7 g. The corresponding hydrochloride melts at 266 C. (with decomposition (from isopropanol)).

Example 4.7-beta-phenyl-granatanol-(3-beta) 34.4 grams of the 7-beta-phenyl-pseudopelletierine obtained according to the procedure of Example 1 are dissolved in 600 ml. of ethanol 47 grams of sodium in small portions are slowly added to the solution whereupon the mixture begins to boil. When all the sodium has been dissolved, the mixture is refluxed for one hour. 100 ml. of Water are added, and the resulting mixture is concentrated to A1 of its volume. Thereafter 500 m1. of water are added to the resulting concentrate and the mixture is extracted with methylene chloride. The extract is dried and concentrated. 28.4 grams of 7-beta-phenyl-granatanol-(3-beta) having a melting point of 129-130 C. (from petroleum ether having a boiling point of 100-140 C.) are obtained as a residue. The yield amounts to 81.8%. The corresponding hydrochloride melts at 280-281 C. (from ethanol).

Example 5 .7-beta-phenyl-3-alpha-acet0xy-granatane 21.5 ml. of acetyl chloride are slowly added to a solution of 34.7 g. (0.15 mol) 7-beta-phenyl-granatanol-(3- alpha) (obtained according to the procedure set out in Example 3) and 28 g. tri-n-butylamine in 170 ml. benzene, and the resulting mixture heated for 4 hours under reflux. Thereafter the excess acetyl chloride is decomposed with 200 ml. of water, and the mixture is made alkaline with caustic soda solution and extracted with benzene. The resulting extract is concentrated and the concentrate distilled. From the distillation there are obtained 36.6 g. 7-beta-phenyl-3-alpha-acetoxy-granatane having a boiling point M of 160-185 C. The yield amounts to 78.9%. The corresponding hydrochloride prepared in the conventional manner melts at 236-238" C. (from isopropanol).

Example 6 .N -benzy l-7-beta-pheny l-norgrana mnone- (3) 2-ethoxy-4-phenyl-3,4-dihydro-2H-pyrane is hydrolyzed by the procedure set out in Example 1, Method 1, above and reacted With acetone dicarboxylic acid and benzylamine at a pH of 3-4. N-benzyl-7-beta-phenyl-norgrana- 1 tanone-(3) having a boiling point of 228-235 C. and a melting point of 89-91 C. (from petroleum ether) is; thereby obtained with a yield of 35.4%. The corresponding hydrochloride melts at 239 C. (with decomposition (from isopropanol) Example 7 .N-benzyI-S-beta-phenyl-norgra'natane 23.7 grams of the N-benzy1-7-beta-phenyl-norgranatanone-(3) prepared according to the procedure of Example 6'are added to a mixture of 15.5 ml. hydrazine hydrate, 1.6 ml. water, 15.5 g. potassium hydroxide and ml. triglycol. The mixture is slowly heated with stirring to 25 0C. Any easily volatile products are condensed and separated by means of a descending condenser. The remaining reaction mixture is diluted with 400 ml. Water and extracted with chloroform. The extract is dried and concentrated. The concentrate is distilled. 13.0 grams of N-benzyl-3-beta-phenyl-norgranatane having a boiling point of 205215 C. are obtained. The yield amounts to 57.5%. The base recrystallized from methanol has a melting point of 84-86 C. The hydrochloride melts at ZOO-202 C. (from methyl ethyl ketone) As can be seen from the table in all of the test PI'O? cedures the standard compound 3-beta-pheny1-tropane was found to be 2-3 times less effective than the corresponding granatane. The toxicity in the mouse and the rat is a direct consequence of the nicotine-like stimulation,

Example 8' N-myl 7-bem-phenylnorgmnamnone(3) 5 and therefore, it must be considered as a measure of the Following the Procedure Set out in Example 1 aholle effectiveness of the substances. Compounds, 7-beta-phen- (Method the y y of Y' 'P Y yl-granatanol-(3-alpha) and 7-beta-phenyl-3-alpha-acety 'plf is reacted With acetone dicarhoxyhc acid oxy-granatane, were found to be less elfective than the and allylemlhe at 3 P of A 423% Yleld of compounds 7-beta-phenyl-granatanone-(3) and 3-betaethyl-3'heta'phehylhorgrahatanohe(3) having a boiling l0 phenyl-granatane with respect to blood pressure increas- P oa of f a melting Point of ing eifect, but were more effective in maintaining the (from Petroleum thus ohtalhed- The y effect, to wit, following intravenous injection of these chloride melts at (With decomposition (from compounds inthe cat, the blood pressure increase persisted methanol and a little 15 for a substantially longer period.

In order to evaluate the therapeutic effectiveness of the A di to the invention, h novel 3 1. compounds of the invention, namely their efiectfm granatane derivatives may be used to provide compositions ministration, comprising both the resultant aetivlty and for use in the treatment of hypotension. The 3-beta-phentoXieitY, it y, the following Procedlltes were Conducted! yl-granatane derivatives may be associated with a carrier Acute ioxieiiy in the mower-The test Compounds which may be either a solid material or a sterile parenteral were injected intravenously and the LD-SO was determined h ii The compositions may take the form of tablets, 24 hours after injection. powders, capsules, or other dosage forms, which are par- Acute forfeit) in the Tats, under urethane ticularly useful for oral ingestion. Liquid diluents are narcosis, the test compounds were intravenously infused employed in Sterile condition for Parenteral use, that is, until the animals were killed. Each of the results, given 25 by injeotiom Such a medium may be a Sterile Solvent in this respect in the table, represents an average of 45 Such as waton The compositions may take the form of eXPenmehtS- active material, namely 3-beta-phenyl-granatane deriva- Blood Pressure increase in the "f blood P tive, mixed with a solid or liquid diluent, with or with- W measured during thehtftal'mmahoh of the acute out further agitants. The percentage of active ingredient tOXlCltY- It was Observed that 1t lhcrfiaseh at first and then in the composition may be varied. It is necessary that the decfeased toward the f of the lhfhsloh- The doses active ingredient constitute proportions such that a suit- Whlch Produced ah optimum blood Pressre Increase are able dosage will be obtained. Obviously, several unit Set t In t tabledosage forms may be administered at about the same time.

(4) Circulatory efiect m the the the Activity increases with concentration of phenyl-granatane travenous injectlon of the test compounds was observed derivative with respect to increase in blood pressure. An increase What is claimed is: in blood pressure and vascular resistance of varying dura- L 7 beta pheny1 granatanorw tioh was obsefved' 2. 3-beta-phenyl-granatane.

The following table shows the doses WhlCh produced an 7 h 1-g anatano1-(3-alpha) optimum increase in blood pressure without concomitant 4O 7 beta phenyl granatano1 (Nada) toxlc phenomhna' 5. 7 beta-phenyl-3-alpha-acetoxy-granatane.

The .fouowmg ounds of the Invention were 6. A chemical compound represented by the structural ployed 1n the evaluat1on: formula:

A-= 7-beta-phenyl-granatanone- 3 4 r A B=3-beta-phenyl-granatane C:7-beta-phenyl-granatanol-(El-alpha) D=7-beta-phenyl-granatanol-(3-beta) N E=7-beta-phenyl-3-alpha-acetoxy-granatane In addition compound F (3-beta phenyltropane) which constitutes a tropane derivative was employed as a. standard and basis of comparison. Its blood pressure increasing effect on dogs has been described by Lands and Archer (Journal of Medicinal and Pharmaceutical Chemistry 2, 449460, 1960).

112) Q- N-CH: \=R

TABLE Optimum blood pressure increasing doses LD-50 LD-50 Compound R 12 Mouse, Rat,

tg-I e- Mia/ g Cat 1.v. 1.v. I 712,

h MgJkg. Min.

= 1 10.5 18.8 9.4 1.0 5 z 1 0. 45 0. 17 0.14 0.05 5 HOH 1 27.5 32.5 9.4 2.0 20 HOHB 1 24.5 2.0 13000011 1 14.6 32.5 7.1 3.0 20 11 0 1.16 2.12 o. 43 o. 15 5 1 7-beta-3-alpha-form. t 7-betar3-betaiorm. 7-beta-3-alpha-lorm.

7 8 wherein R is a member selected from the group consisting 2,425,320 8/ 1947 Hill 252-449 of hydrogen, methyl, benzyl, and allyl, and A is a member 2,606,155 8/1952 Hill 252149 selected from the group consisting of a carbonyl group 2,932,646 4/1960 Biel 260--294.7 CO) and a hydroxymethylene group CHOH). 2,956,059 10/1960 Renz et a1. 26()-294.3 7. N-benzyl-7-beta-phenyl-norgranatanone-(3). 5 2,986,573 5/1961 Topliss et a1. 16765 8. N-benzy1-3-betaphenyl-norgranatane. 2,987,442 6/ 1961 McLean et a1. 167-65 9. N-ai1y1-7-beta-phenyl-norgranatanone (3).

OTHER REFERENCES References Cited by the Examiner Cope et al., I. Am. Chem. Society," vol 73, pages UNITED STATES PATENTS 3419 3424 (1951) 1,915,334 6/1933 Salzberg et a1 260-243 2,075,359 3/1937 Salzberg et a1 16722 NICHOLAS S. RIZZO, Primary Examiner. 

2. 3-BETA-PHENYL-GRANATANE
 6. A CHEMICAL COMPOUND REPRESENTED BY THE STRUCTURAL FORMULA: 